The present invention, in some embodiments thereof, relates to a method of treating lipid-related disorders and, more particularly, but not exclusively, to fatty liver disorders.
Non-Alcoholic Fatty Liver Disease (NAFLD) affects 30% of adults in the US and is a key predisposing factor for nonalcoholic steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma. NAFLD is accompanied by hyperlipidemia and is strongly associated with insulin resistance, obesity and type 2 diabetes. However, the mechanisms initiating this pathogenesis are not fully understood, and the available therapeutic interventions are of limited efficacy. NAFLD is characterized by accumulation of triglyceride lipid droplets in the cytoplasm of liver hepatocytes, yet the processes promoting this accumulation are still not understood.
In both the liver and the brain, control of metabolism is governed by a complex transcriptional system, in which microRNAs (miRNAs) function as critical regulators. MiRNA precursors (stem-and-loop molecules generated from a primary transcript) are cleaved to 22-bp mature double-stranded forms, one of which guides the complex to a partially complementary sequence often found in the 3′-untranslated region (3′-UTR) of target genes. The miRNA 5′-end ‘seed’ region determines target specificity and decides between mRNA cleavage and translational repression. Promiscuous complementation enables one miRNA to target more than one mRNA and achieve gene-network-level regulation. In the mammalian immune system, miRNAs control both differentiation and innate and adaptive immune responses. Each miRNA may target several mRNAs, often in specific locations on their 3′-UTR and can modulate entire pathways in a rheostat-like manner. MiRNAs act rapidly and effectively to block expression of their multiple target transcripts and operate at the network level, suggesting that they are particularly suitable for hierarchically controlling the rapidly adjustable physiology of entire physiological systems. Moreover, due to the multileveled regulation of a physiological system, very low concentrations of specific miRNAs could modulate multiple inputs such as both neuronal and immune pathways.
miR-132 has been identified as a hierarchically high regulator of such pathways (Soreq and Wolf, 2011, Trends Mol Med 17(10): 548-555; Shaltiel et al., 2013, Brain Struct Funct 218(1): 59-72; Greenberg and Soreq, 2014, Curr Pharm Des).
WO 2013034653 teaches administration of anti-miR-132 agents for the treatment of various diseases including liver disease.
Westenskow et al. (Invest Ophthalmol Vis Sci 2012; 53: E-Abstract 4120) teaches administration of anti-miR-132 agents for the treatment of eye disorders.
U.S. Patent Application No. 20120178791 teaches administration of anti-miR-132 agents for the treatment of HCMV.